BIMODAL FUNCTION OF ASTROGLIA IN SCA1 DISEASE PROGRESSION Spinocerebellar ataxia type 1 (SCA1) is a fatal autosomal dominant disease that has no available treatment options for patients. SCA1 is caused by a tandem polyglutamine (polyQ) repeat expansion in the Ataxin-1 protein that leads to progressive degeneration mainly in cerebellar Purkinje neurons. The subsequent degeneration of Purkinje cell neuron underlies the progressive ataxia and loss of fine motor control found in patients. Due to the progressive atrophy of Purkinje neurons, research has focused on neuronal cell intrinsic factors that lead to dysfunction and degeneration while little is known about how Purkinje cell non-intrinsic factors contribute to SCA1 disease state. Recently, we have shown that astroglia, and in particular Bergmann glia, become reactive before any Purkinje cell atrophy occurs in both a transgenic (82Q) and knock-in (154Q) mouse model of the disease, which is suggestive of a possible role of astroglia in SCA1 pathogenesis. Bergmann glia, the most prominent astroglial subtype in the Purkinje cell layer of the cerebellum, normally function as supportive cells that, among other roles, maintain potassium and glutamate equilibriums. Yet, how these functions are changed by astrogliosis in SCA1 remains unclear. Therefore, the goal of this proposal is to assess the possible mechanisms by which astroglia, in particular Bergmann glia, could contribute to SCA1 disease progression in both mouse models of SCA1. We aim to uncover possible beneficial or maladaptive roles of Bergmann glia using single-cell gene profiling coupled with electrophysiological characterization of Bergmann glia throughout SCA1 disease progression. We hypothesize that there is a bimodal function of Bergmann glia in SCA1, where early phase activation enhances neuroprotective gene expression of potassium inward rectifier 4.1 (Kir4.1) as well as increases potassium buffering. We also hypothesize that long term activation becomes maladaptive and Kir4.1 expression will be downregulated. The downregulation of Kir4.1 would then lead to dysfunctional potassium buffering and glutamate uptake resulting in alterations in calcium signaling as well as membrane potential. The hypothesis that bimodal gene expression of Kir4.1 is neuroprotective early and neurodestructive late in disease will be tested with rescue and knockdown experiments. These studies will not only elucidate non-neuronal gene targets for therapeutics in SCA1, but also it is possible that these findings will be applicable to astrogliosis in other central nervous system diseases.